Identification of molecular target of high risk pediatric AML by comprehensive genetic analysis

• Project/Area Number: 16K20951
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics; Hematology
• Research Institution: Yokohama City University (2017-2018); Gunma University (2016)
• Principal Investigator: SHIBA NORIO 横浜市立大学, 医学部, 講師 (50600615)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 小児 / 急性骨髄性白血病 / DNAメチル化 / 抑制性ポリコーム / 遺伝子発現 / 治療層別化 / 予後予測 / メチル化アレイ / 遺伝子発現解析 / メチル化アレイ解析 / プロテオーム解析 / 遺伝子変異解析

Outline of Final Research Achievements

Lots of gene alterations were identified and used for risk stratification by next generation sequencing. We investigated genome-wide DNA methylation patterns in pediatric patients with AML, and enabled to predict the prognosis particular in patients with FLT3-ITD which was known as adverse prognostic marker.
Surprisingly, when we examined the relation between high PRDM16 expression and PRDM16 methylation sites, most of hypermethylatedion sites were gene body, and located at important regions which were the targets of repressed polycomb in leukemic blast cells.

Academic Significance and Societal Importance of the Research Achievements

小児、成人を問わず、急性骨髄性白血病は予後不良疾患であるが、今回の解析結果は、今後、不必要な造血幹細胞移植を回避したり、新たな分子標的薬の導入やメチル化阻害剤の適応症例の抽出などを可能とする可能性がある。その結果、治療成績の向上、移植治療関連死亡や治療関連の後遺症、合併症を減らすことができ、QOL向上に繋がることが期待される。

Research Products

• [Journal Article] Whole transcriptome sequencing reveals a KMT2A‐USP2 fusion in infant acute myeloid leukemia (2019)
  • Author(s): Ikeda Junji、Shiba Norio、Tsujimoto Shin‐ichi、Yoshida Masanori、Nakabayashi Kazuhiko、Ogata‐Kawata Hiroko、Okamura Kohji、Takeuchi Masanobu、Osumi Tomoo、Tomizawa Daisuke、Hata Kenichiro、Kiyokawa Nobutaka、Ito Shuichi、Kato Motohiro
  • Journal Title: Genes, Chromosomes and Cancer Volume: in press Issue: 9 Pages: 1-1
  • DOI: 10.1002/gcc.22751
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and biological features of paediatric acute myeloid leukaemia (AML) with primary induction failure in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. (2019)
  • Author(s): Miyamura T, Moritake H, Nakayama H, Tanaka S, Tomizawa D, Shiba N, Saito AM, Tawa A, Shimada A, Iwamoto S, Hayashi Y, Koike T, Horibe K, Manabe A, Mizutani S, Taga T, Adachi S.
  • Journal Title: Br J Haematol. Volume: 19 Issue: 2 Pages: 284-288
  • DOI: 10.1111/bjh.15799
  • Peer Reviewed
• [Journal Article] Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia (2018)
  • Author(s): Matsuo Hidemasa、Itonaga Hidehiro、et al.
  • Journal Title: Blood Advances Volume: 2 Issue: 21 Pages: 2879-2889
  • DOI: 10.1182/bloodadvances.2018019398
  • NAID: 120006534600
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic aberrations and new treatment strategies for pediatric acute myeloid leukemia (2018)
  • Author(s): 柴 徳生
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 10 Pages: 2260-2267
  • DOI: 10.11406/rinketsu.59.2260
  • NAID: 130007496727
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Comparison of conditioning regimens for autologous stem cell transplantation in children with acute myeloid leukemia: A nationwide retrospective study in Japan (2018)
  • Author(s): Sakaguchi Hirotoshi、Muramatsu Hideki、Hasegawa Daiichiro、Kudo Kazuko、Ishida Hiroyuki、Yoshida Nao、Koh Katsuyoshi、Noguchi Maiko、Shiba Norio、Tokimasa Sadao、Fukuda Takhiro、Goto Hiroaki、Miyamura Takako、Nakazawa Yozo、Hashii Yoshiko、Inoue Masami、Atsuta Yoshiko、et al
  • Journal Title: Pediatric Blood & Cancer Volume: 66 Issue: 1
  • DOI: 10.1002/pbc.27459
  • Peer Reviewed / Open Access
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for children and adolescents with high-risk cytogenetic AML: distinctly poor outcomes of FUS-ERG-positive cases (2018)
  • Author(s): Tomizawa Daisuke、Yoshida Masanori、Kondo Tadakazu、Miyamura Takako、Taga Takashi、Adachi Souichi、Koh Katsuyoshi、Noguchi Maiko、Kakuda Harumi、Watanabe Kenichiro、Cho Yuko、Fukuda Takahiro、Kato Motohiro、Shiba Norio、Goto Hiroaki、Okada Keiko、Inoue Masami、Hashii Yoshiko、Atsuta Yoshiko、Ishida Hiroyuki
  • Journal Title: Bone Marrow Transplantation Volume: 54 Issue: 3 Pages: 393-401
  • DOI: 10.1038/s41409-018-0273-7
  • Peer Reviewed
• [Journal Article] RUNX1 mutations in pediatric acute myeloid leukemia are associated with distinct genetic features and an inferior prognosis. (2018)
  • Author(s): 1.Yamato G, Shiba N, Yoshida K, Hara Y, Shiraishi Y, Ohki K, Okubo J, Park MJ, Sotomatsu M, Arakawa H, Kiyokawa N, Tomizawa D, Adachi S, Taga T, Horibe K, Miyano S, Ogawa S, Hayashi Y.
  • Journal Title: Blood Volume: Epub Issue: 20 Pages: 2266-2270
  • DOI: 10.1182/blood-2017-11-814442
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study. (2018)
  • Author(s): Shimada A, Iijima-Yamashita Y, Tawa A, Tomizawa D, Yamada M, Norio S, Watanabe T, Taga T, Iwamoto S, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Goto H, Kosaka Y, Saito AM, Kiyokawa N, Horibe K, Hara Y, Oki K, Hayashi Y, Tanaka S, Adachi S.
  • Journal Title: Int J Hematol. Volume: 107(5) Issue: 5 Pages: 586-595
  • DOI: 10.1007/s12185-017-2395-x
  • Peer Reviewed
• [Journal Article] Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. (2017)
  • Author(s): Hara Y, Shiba N, Ohki K, Tabuchi K, Yamato G, Park MJ, Tomizawa D, Kinoshita K, Shimada A, Arakawa H, Saito AM, Kiyokawa N, Tawa A, Horibe K, Taga T, Adachi S, Taki T, and Hayashi Y.
  • Journal Title: Genes, Chromosomes & Cancer Volume: 14 February 2017 Issue: 5 Pages: 394-404
  • DOI: 10.1002/gcc.22444
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ASXL2 Mutations are Frequently Found in Pediatric AML Patients with t(8;21)/RUNX1-RUNX1T1 and Associated with a Better Prognosis. (2017)
  • Author(s): Yamato G, Shiba N, Yoshida K, Shiraishi Y, Hara Y, Ohki K, Okubo J, Okuno H, Chiba K, Tanaka H, Kinoshita A, Moritake H, Kiyokawa N, Tomizawa D, Park MJ, Sotomatsu M, Taga T, Adachi S, Tawa A, Horibe K, Arakawa H, Miyano S, Ogawa S, Hayashi Y.
  • Journal Title: Genes Chromosomes Cancer. Volume: - Issue: 5 Pages: 382-393
  • DOI: 10.1002/gcc.22443
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Outcome of relapsed core binding factor acute myeloid leukemia in children: A result from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05R study. (2017)
  • Author(s): Moritake H, Tanaka S, Nakayama H, Miyamura T, Iwamoto S, Shimada A, Terui K, Saito A, Shiba N, Hayashi Y, Tomizawa D, Taga T, Goto H, Hasegawa D, Horibe K, Mizutani S, Adachi S.
  • Journal Title: Pediatr Blood Cancer Volume: 64(10) Issue: 10
  • DOI: 10.1002/pbc.26491
  • Peer Reviewed
• [Journal Article] Clinical features and prognostic impact of PRDM16 expression in adult acute myeloid leukemia (2017)
  • Author(s): Yamato Genki、Yamaguchi Hiroki、Handa Hiroshi、Shiba Norio、Kawamura Machiko、Wakita Satoshi、Inokuchi Koiti、Hara Yusuke、Ohki Kentaro、Okubo Jun、Park Myoung-Ja、Sotomatsu Manabu、Arakawa Hirokazu、Hayashi Yasuhide
  • Journal Title: Genes, Chromosomes and Cancer Volume: 56 Issue: 11 Pages: 800-809
  • DOI: 10.1002/gcc.22483
  • Peer Reviewed
• [Presentation] Clinical significance and prognostic analyses of PTPN11, RAS, and CBL mutations in pediatric AML -the JCCG study, JPLSG AML05- (2018)
  • Author(s): Taeko Kaburagi, Genki Yamato, Norio Shiba, Yusuke Hara, Kentaro Ohki, Manabu Sotomatsu, Hirokazu Arakawa, Nobutaka Kiyokawa, Daisuke Tomizawa, Souichi Adachi, Takashi Taga, Keizo Horibe, Yasuhide Hayashi.
  • Organizer: 日本血液学会
• [Presentation] Prognosis of pediatric AML patient with FLT3-ITD is predicted by DNA methylation pattern; the JCCG study, JPLSG AML05 (2018)
  • Author(s): Genki Yamato, Tomoko Kawai, Norio Shiba, Kentaro Ohki, Yusuke Hara, Nobutaka Kiyokawa, Daisuke Tomizawa, Akira Shimada, Manabu Sotomatsu, Hirokazu Arakawa, Souichi Adachi, Takashi Taga, Keizo Horibe, Kenichiro Hata, Yasuhide Hayashi.
  • Organizer: 世界小児がん学会
  • Int'l Joint Research
• [Presentation] 3.Comprehensive Analysis of 343 Genes using Targeted Sequencing Panel by Next-Generation Sequencer In 77 Pediatric AML Patients with Normal and Complex Karyotypes: JCCG Study, JPLSG AML-05. (2018)
  • Author(s): Genki Yamato, Norio Shiba, Kenichi Yoshida, Yusuke Hara, Yuichi Shiraishi, Kentaro Ohki, Manabu Sotomatsu, Hirokazu Arakawa, Hidemasa Matsuo, Akira Shimada, Nobutaka Kiyokawa, Daisuke Tomizawa, Takashi Taga, Keizo Horibe, Satoru Miyano, Seishi Ogawa, Souichi Adachi, Yasuhide Hayashi
  • Organizer: 米国血液学会
  • Int'l Joint Research
• [Presentation] 4.Allogeneic bone marrow versus peripheral blood stem cell transplantation for hematological malignancies in children: systematic review and meta-analyses. (2018)
  • Author(s): Yuko Shimosato-Wada, Reo Tanoshima, Shin-ichi Tsujimoto, Masanobu Takeuchi, Norio Shiba, Tohru Kobayashi, and Shuichi Ito.
  • Organizer: 米国血液学会
  • Int'l Joint Research
• [Presentation] RNA sequencing illustrates the genetic backgrounds of pediatric acute myeloid leukemia: the result of the JCCG study, JPLSG AML-05 (2017)
  • Author(s): Norio Shiba, Kenichi Yoshida, Yusuke Hara, Genki Yamato, et al.
  • Organizer: 第59回米国血液学会（ASH）
  • Int'l Joint Research
• [Presentation] Comprehensive Methylation Analysis in Pediatric Patients with Acute Myeloid Leukemia. (2017)
  • Author(s): enki Yamato, Tomoko Kawai, Norio Shiba, Kentaro Ohki, et al.
  • Organizer: 第59回米国血液学会（ASH）
  • Int'l Joint Research
• [Presentation] Clinical Features and Prognostic Impact of RUNX1 and PTPN11 Mutations in Pediatric Acute Myeloid Leukemia ;the JCCG study, -JPLSG AML-05- (2017)
  • Author(s): Genki Yamato, Norio Shiba, Kenichi Yoshida, Yusuke Hara, et al.
  • Organizer: 第59回米国血液学会（ASH）
  • Int'l Joint Research
• [Presentation] Biology and Prognostic Markers in Young Children with Acute Myeloid Leukemia -the Jccg Study, JPLSG AML-05- (2017)
  • Author(s): Yusuke Hara, Norio Shiba, Ken Tabuchi et al.
  • Organizer: 第59回米国血液学会（ASH）
  • Int'l Joint Research
• [Presentation] Transcriptome Analysis Revealed the Entire Genetic Understanding of Pediatric Acute Myeloid Leukemia with a Normal Karyotype (2016)
  • Author(s): Shiba N, Yoshida K, Shiraishi Y, Hara Y, Yamato G, Kaburagi K, Sanada M, Ohki K, Park MJ, Tomizawa D, Chiba K, Tanaka H, Sotomatsu M, Arakawa H, Horibe K, Taga T, Adachi S, Tawa A, Miyano S, Ogawa S and Hayashi Y.
  • Organizer: 58th Annual Meeting of the American Society of Hematology（ASH)
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Identification of two distinct poor prognostic subgroups related to high expression of BMP2 or PRDM16 in pediatric AML (2016)
  • Author(s): Hara Y, Yamato G, Shiba N, Okubo J, Ohki K, Park MJ, Sotomatsu M, Tomizawa D, Taki T, Kinoshita A, Kiyokawa N, Taga T, Arakawa H, Tawa A, Horibe K, Adachi S and Hayashi Y
  • Organizer: 58th Annual Meeting of the American Society of Hematology（ASH)
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Retrospective Evaluation of Correlations Between Genetic Backgrounds and Stem Cell Transplantation for De Novo Pediatric Acute Myeloid Leukemia (2016)
  • Author(s): Kaburagi T, Yamato G, Shiba N, Hara Y, Ohki K, Ichikawa H, Park MJ, Shimada A, Sotomatsu M, Arakawa H, Horibe K, Adachi S, Taga T, Tawa A, Hayashi Y
  • Organizer: 58th Annual Meeting of the American Society of Hematology（ASH)
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Integrated genetic analysis using next generation sequencing in pediatric AML (2016)
  • Author(s): 柴 徳生
  • Organizer: 第75回日本がん学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
  • Invited